The Role of Kdm5d in the Development of Chemoresistance to Cisplatin Through Cul4a in Neuroblastoma

Abstract

Chemoresistance is a major cause of cancer therapy failure. Increasing evidence points to the importance of histone lysine demethylase function, whose dysregulation has been described in many cancers. KDM5, a family of histone lysine demethylases, may play a critical role in downregulation of tumour-suppressors or upregulation of oncogenes and in the development of drug tolerance. In this study, we examined the expression of KDM5D in cell lines derived from high-risk neuroblastoma. We found that KDM5D expression was lost in all cisplatin-chemoresistant neuroblastoma cell lines compared with sensitive parental cells. In addition, we found that the cisplatin-chemoresistant neuroblastoma cell line had increased expression of the ubiquitin ligase cullin 4A (CUL4A) compared with the sensitive parental cells. CUL4A plays a role in cellular processes and its aberrant regulation has been observed in a number of cancers. We have shown that silencing of KDM5D causes a more aggressive phenotype of NBL by promoting cell proliferation and migration, evading cell death, promoting S phase of the cell cycle, and desensitizing sensitive cells to CDDP via the gene CUL4A. In addition, ectopic expression of KMD5D in a cisplatin-resistant cell line reversed these phenomena. Our results suggest that KDM5D and / or CUL4A may be a biomarkers of chemoresistance to cisplatin and a potential therapeutic target in NBL.